Lock and key micelles and monomer building blocks therefor

ABSTRACT

A lock unimolecular micelle includes at least one engineered acceptor specifically binding a ligand (or specifically a &#34;key&#34; unimolecular micelle) thereto. A key unimolecular micelle comprises a core molecule and a plurality of branches extending therefrom, at least one of the branches including a shank portion extending therefrom having a terminal moiety at an end thereof for binding to a complimentary acceptor of a lock unimolecular micelle. Together, the lock and key micelles form a unit, either irreversibly or reversibly bound wherein the lock micelles is a soluble receptor engineered to specifically bind to the specifically engineered key micelle.

GRANT INFORMATION

This invention was made with Government support under National ScienceFoundation Grant Nos. DMR-92-17331; DMR-92-08925; DMR-96-22609 and TheU.S. Army Office of Research Grant No. DAAHO4-93-G-0448. The Governmenthas certain rights in the invention.

This is a continuation-in-part of application Ser. No. 08/280,591, filedon Jul. 25, 1994, now U.S. Pat. No. 5,650,101; issued Jul. 22, 1997.

TECHNICAL FIELD

The present invention relates to highly-branched molecules possessing apredetermined three-dimensional morphology, referred to as unimolecularmicelles. More specifically, the present invention relates to micelleshaving uses in areas such as radio-imaging, drug delivery, catalysis,affinity filtration for separating enantiomers and the like and otherareas.

BACKGROUND OF THE INVENTION

Neat and orderly arrays for micellar systems have been reported,¹,2 andare structurally based on the original work of Vogtle et al.,^(3a) whodelineated "cascade" construction. The U.S. Pat. Nos. 4,435,548, issuedMar. 6, 1984; 4,507,466, issued Mar. 26, 1985; 4,558,120, issued Dec.10, 1985; 4,568,737, issued Feb. 4, 1986; 4,587,329; issued May 6, 1986;4,631,337, issued Dec. 23, 1986; 4,694,064, issued Sep. 15, 1987; and4,737,550, issued Apr. 12, 1988, all to Tomalia et al., relate tobranched polyamidoamines. The polyamidoamines include a plurality ofpendent aminoamide moieties exhibiting properties which are related tolinear polyamidoamines from which the branched polymers are derived.These compounds can be characterized as high molecular weight,highly-branched, multi-functional molecules possessing athree-dimensional morphology. Synthetic strategies employed for therealization of such "cascade polymers"^(3b) require consideration ofdiverse factors including the content of the initial core, buildingblocks, space for molecules, branching numbers, dense packing limits,and desired porosity, as well as other factors.⁴ The selection of thebuilding blocks govern the type of branching desired from the coremolecule, as well as the technology used to attach each successive layeror "tier" of the cascade polymer.

Applicants have developed a novel method of making cascade polymers,especially those providing a unimolecular micelle consisting essentiallyof alkyl carbon possessing diverse terminal functionality. Suchcompounds are disclosed in U.S. Pat. No. 5,154,853 (1992) to applicants.

Further developments of the above-described chemistry by applicants havedemonstrated that the unimolecular micellar character permits theinitial evaluation of the orderliness and chemistry within a series ofspecifically designed, spherical macromolecules due to covalently boundassemblies of internal reactive sites.⁵,6 Similar dendritic species havebeen constructed with amide,⁴,7,8 ethereal,⁹,10 phosphonium,¹¹silicone,¹² germane,¹³ and aryl,¹⁴⁻¹⁹ inner linkages andfunctionalities.

Out of all these systems, however, it has been determined that onlythree systems thus far created have the potential to undergospecifically located chemical modification within the inner lipophilicregions thereof. When there is actual space within these regions, theselipophilic regions are termed "void regions". The sum of the "voidregions" constitutes the total "void volume" of the cascade polymer. Thepresently known compounds having such inner void regions capable ofcovalent modification are the hydrocarbon-constructed cascadeintermediates possessing specifically located internal substituents orunsaturated centers, e.g., dialkylacetylenic moieties, set forth in theabove-captioned patent to applicants (U.S. Pat. No. 5,154,853), thosecompounds disclosed by Moore and Xu,¹⁹ that possess rigid polyalkynespacers, or connectors, between branching centers and are thus prone toincomplete chemical transformations, and hence asymmetry, due to stericinteractions, and those compounds set forth in the Tomalia patents setforth above which are amino-branched compounds having short linkagesbetween branch points (thus minimizing void volume) and internalbridging trialkyl substituted nitrogen atoms possessing less than puresp³ hybridization, making internal nucleophilic substitution difficult.

Applicants have found⁶ that the dialkylacetylene moieties of the cascadepolymers set forth herein are also specifically located withinaccessible void regions. Applicants have shown that molecular guestprobes, including diphenylhexatriene (DPH), phenol blue (PB),naphthalene, chlortetracycline (CTC), and pinacyanol chloride (PC) canbe used as micellar probes to access the infrastructure of such cascadepolymers utilizing known chemistry.²⁰⁻²⁴

Demonstrations of accessibility of void regions to chemical modificationhas led to the development of the ability to manipulate internalmoieties within the spherically symmetrical dendritic macromolecule,after construction, to allow easy incorporation of internally locatedsensitive and/or reactive groups which otherwise would be difficult tointroduce or protect during cascade construction. Specifically, theintroduction of metal and metalloid centers at the interior of cascadeinfrastructures has been accomplished. Such derived compounds, referredto generically as metallospheres, superclusters, unimolecularMetallomicellanes and Nonmetallomicellanes, Metalloidomicellanes,derivatized Micellanes, or Micellanes, can be utilized for drug deliveryof various metals and nonmetals, which are presently difficult todeliver in pharmacologically efficacious matters. The use ofcarrier-metal combinations as pharmacotherapeutic agents has had theproblem of not being able to deliver sufficient metal/nonmetal to a siteat a sufficiently low dose of the carrier of the metal/nonmetal per se.

For example, the U.S. Pat. No. 5,422,379 to applicants' provides a meansof delivering high concentrations of the metal/nonmetal moiety(ies) to asite at a relatively low dose of carrier (Micellane system).

Accessibility to void regions can be achieved by various means.Accessibility can be achieved during synthesis of tiers of themacro-molecular or can be achieved after synthesis by variousmanipulations of the molecule. It has been found that thesemanipulations of the molecule can be achieved by increasing and then,decreasing the size of the molecule.

A further and most significant step has been taken towards specificityin the access of guest molecules to the void regions and binding of theguest therein. Specifically, a "lock and key" concept has been developedpertaining to unimolecular micelles which takes advantage of severaldemonstrated and unique characteristics of these cascademacro-molecules. The advantageous characteristics include: (1) theinternal, constructed, and predetermined or predesigned void domain(s)created within the micelle superstructure, (2) the ability to gainfacile access to these inner void regions with molecular guest(s) togenerate a micellar complex and possibly multimicellar complexescomprised of one or more hosts with one or more guests, (3) the abilityto incorporate specific acceptor moieties into the structure of one ormore arms, branches, or cascade building blocks or the syntheticactivation of a dormant, or masked acceptor loci thereby affixing theacceptor moieties permanently, or for a controlled period of time, and(4) the unique homogenous structure and topology of the building blockswhich allow the incorporation of predesigned acceptor moieties onto oneor more of the unimolecular micelle branches. In other words, anacceptor region which will bind specifically to a complementary moietycan be engineered per se and then specifically disposed andpreferentially exposed to the complementary moiety for irreversible orreversible binding thereto. Further, the micellar structure can containan otherwise soluble receptor (acceptor region) and render the receptorsoluble by virtue of soluble components on the micelle surface.

Utilizing these molecules, the present invention can provide formolecular recognition and binding in and between two or more micelles.This is specific binding of a key micelle with a lock micelle, thebinding being selective as well as being able to be turned on and turnedoff.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a lockunimolecular micelle including at least one engineered acceptor forspecifically binding a ligand thereto.

The present invention further provides a key micelle molecule comprisinga core molecule and a plurality of branches extending therefrom. Atleast one of the branches includes a shank portion extending therefromhaving a terminal moiety at the end thereof for binding to acomplementary acceptor of a lock unimolecular micelle.

The present invention further provides a method of generating aunimolecular complex by combining a lock micelle molecule including atleast one engineered acceptor within a solution containing the keymicelle molecule and selectively binding the terminal moiety of the keymicelle molecule to the acceptor of the lock micelle to selectively forma bimolecular complex.

In accordance with the present invention, there is provided a method ofmaking a physicochemically operative monomer building block forsynthesis of a cascade polymer including the steps of isolating aphysicochemically operative moiety including an amino group and a multi-branched core alkyne building block including an amino group withbis(acid chloride) to form a physicochemically operative bis amidemonomer including a physicochemically active portion and a branchportion.

The present invention further provides a monomer building block of theformulas ##STR1## is a physicochemically operative moiety.

BRIEF DESCRIPTION OF THE DRAWINGS

The file of this patent contains at least one drawing executed in color.Copies of this patent with color drawings(s) will be provided by thePatent and Trademark Office upon request and payment of necessary fee.

Other advantages of the present invention will be readily appreciated asthe same becomes better understood by reference to the followingdetailed description when considered in connection with the accompanyingdrawings wherein:

FIG. 1 shows some representative lock and key designs (column 1) and theconcept of a specific key associating with a specific lock (column 2)(T. J. Murray, and S. C. Zimmerman J. Am. Chem. Soc. Vol 114., pp4010-4011, 1992). The third column abstractly depicts the arrangement ofpartial positive and negative charges that are responsible for themolecular recognition inherent in the lock and key design. It should benoted that the lock and key concept is not limited to systems with threehydrogen bonds. The incorporation of sites in locks and keys thatcontain more or less donor/acceptor sites is envisioned.

FIG. 2 shows a space filling model of a hydrocarbon based cascademacromolecule in the expanded and contracted form. In the expanded view,the interior core is clearly visible, whereas, in the contractedconformation the central core is obscured from view and hence much moreprotected from the environment than when it is expanded.

FIG. 3 illustrates the use of hydrocarbon-based building blocks, such asthe acid chloride tris(benzyl ether), for the construction offour-directional dendritic macromolecules. The use of standardamine-acid chloride chemistry allows the introduction of thediaminopyridine acceptor unit (A) into the cascade framework.

FIG. 4 depicts a versatile method for the construction offour-directional cascade locks containing four diaminopyridine units (A)equidistant from the central core (II and III). Theaminopyridinetriester building block used for the construction of thedendritic arms is prepared via high dilution methodology that allows theincorporation of various alkyl chain lengths separating the triester andaminopyridine moieties. This feature allows the design of buildingblocks that introduce varying degrees of lipophilicity to the interiorcascade superstructure. Standard formic acid mediated tert-butyl esterconversion to acid functionalities allows the formation of water-solublelocks as well as generates the poly(acid) precusor for the addition ofanother tier, or layer, of cascade building block in the depicted case,the aminotris(tert-butyl ester)! via standard peptide-type couplingconditions. It should be noted however that other amino/ester buildingblocks can be added to the poly(acids), such as the previously describedaminopyridinetriester, via the same technology.

FIG. 5 illustrates the docking motif of the lock (III) and the bitportion of a generalized key. In this case, the bit (IV) is constructedof barbituric acid or any derivative thereof. Since there are fourdiaminopyridine units incorporated into the dendritic structure, up tofour equivalents of key can be constrained to the cascade framework (V).

FIG. 6 shows the lock and key motif (V) whereby the bit of the key isconnected to a "shank" (in this case depicted as a hydrocarbon chain)which is further connected to a "bow" or "head" (Z) of the key. Z can beenvisioned as being any group or functionality that can logicallyconnected to the bit through the shank. This can include another cascadestructure that can be designed to enhance (or hinder) aqueous (ororganic) solubility.

FIG. 7 demonstrates some of the versatility and latitude in designingcascade "locks and keys" in that the donor/acceptor moieties may easilybe reversed. However, the hydrogen bonding that results from the lockand key connectivity is the same and is based on similar molecularrecognition.

FIG. 8 illustrates the construction of locks and keys based on covalentmetal-ligand bonding. As depicted, one lock site can be attached to agrowing cascade structure via the connection of a terpyridine moiety toa carboxylic acid which can then be subjected to the standard amidecoupling and ester deprotection methods that have been previouslydescribed.

FIG. 9 illustrates the potential to incorporate multiple donor/acceptorsites onto a branch(s) of the cascade superstructure.

FIG. 10 shows a line drawing of the complex (VI) formed when thirdgeneration lock is treated with a second generation key.

FIG. 11 shows a three-component reaction for the preparation of buildingblocks possessing a H-bonding, molecular recognition site, wherein thereagents are THF, Et(i-Pr)₂ N, 0°-25° C., 24 hours.

FIG. 12 shows construction of first and second tier utilitariandendrimers possessing four 2,6-diamidopyridine units, wherein thereagents are THF, Et(i-Pr)₂ N, 0°-25° C., 12 hours;b) HCO₂ H, 35° C., 18hours;c) aminotriester 1, DCC, 1-HBT, DMF, 25° C., 12 hours.

FIG. 13 shows ¹ H NMR titration data plotted for the determination ofglutarimide:building block 3(a) and 4(b)! and dendrimer 6a(c)! H-bondingassociation constants.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a lock and a key unimolecular micelle.The lock unimolecular micelle includes at least one engineered acceptorfor specifically binding a ligand, such as a key unimolecular micellethereto.

The term "lock micelle" means a unimolecular micelle including anacceptor region for specifically binding, with a predetermined affinityto a specific complimentary site of a ligand, the acceptor beingdisposed within an engineered void region of the micelle which furtherdefines a pocket which allows entrance thereto of the same specificligand, based on the ligands secondary and tertiary structure.

The term "key micelle" refers to specific ligands which are engineeredmicelles having the binding region which is complimentary to theaforementioned receptor (acceptor region) and a secondary and tertiarystructure allowing entrance thereof with the void region of the lockmicelle containing the receptor.

Thus the lock and key concept requires a combination of access of thekey micelle region including the binding area into the void region ofthe lock micelle, and then affinity of the acceptor region to thebinding region of the key micelle. This allows for competitive bindingbetween key micelles for a receptor, as well as with naturally occurringligands, such as drugs, or the like, for the acceptor. It also allowsfor competitive binding between the lock micelle and natural receptorsfor specific drug as the binding region, such as a barbiturate, andrelease the drug bound key micelle at a naturally occurring receptorhaving a higher affinity therefore in an equilibrium environment.

More specifically referring to the micellar structure, the presentinvention is provides a unimolecular micelle including internal voidareas, the void areas including reactive sites capable of covalent andnoncovalent bonding to guest(s). The unimolecular micelles of thepresent invention are cascade polymers which act as micelles. Suchunimolecular micelles can be generally in the form of those disclosed inU.S. Pat. No. 5,154,853 to applicants, cited above, being all alkylmolecules, or in the form of those disclosed in the Tomalia patentsdiscussed above, having a nitrogen core or branching site. Suchcompounds have pre-defined branching, depending upon the number ofsequential tier additions that are performed in accordance with theabove-cited references. The etymology of the term "Micelle", as employedin the classical or usual sense, refers to a noncovalently associatedcollection (aggregate) of many simple molecules functioning as a unithaving unique properties (e.g., aqueous solubilization of waterinsoluble materials) that are not observed with the individual moleculeswhich comprise the micelle; whereas as used herein, unimolecular micelleor micellane refers to a single macromolecule, possessing a covalentlyconstructed superstructure, that can perform the same function(s)⁶ as aclassical micelle. Additions to these terms denote the incorporation ofspecific types of metals or nonmetals within the chemically accessiblelipophilic interior of the unimolecular micelle. The term ligand ismeant to describe any site that has the ability to donate electrondensity, such as a pair of electrons to a metal or nonmetal moiety, thusforming a covalent or noncovalent bond. Most often the term is used whendiscussing metals that are bonded, or complexed, to atoms, such as N, P,0, and/or S. The term guest(s) is (are) meant to describe any metal ornonmetal (or any reasonable combination thereof) specie(s) that can beintroduced into or onto the cascade framework. The introduction can beirreversible due to the formation of covalent bonds or reversible due tothe formation of noncovalent bonds that are easily broken (e.g.,hydrogen bonds) or the reversibility may be due to lipophilic-lipophilicand hydrophilic-hydrophilic attractions.

Micelles made in accordance with the present invention can be describedas having at least one core atom, preferably a carbon atom, and armsbranching from the core atom. At least one acceptor is an integral partof at least one of the branches for binding at least a portion of theligand within the void region. At least some of the branches can extendabout the acceptor defining a predetermined pocket containing the voidregion. Accordingly, the pocket is a lipophilic container of the voidregion and acceptor and defines an opening to the exterior of themicelle from the void region. That is, the branches form a lipophilicwall of a cave in which the acceptor is exposed. Such a pocket can beengineered to include one or more acceptor sites as described below.Further, the acceptor sites can be engineered into any branching tier ortiers as needed to engineer a specifically defined receptor or dockingsite which is complementary to the tertiary and quaternary structure ofthe ligand to be bound. As it will be described below, the ligand can bein the form of a specifically engineered key micelle such that the keyinserts into the pocket and includes a terminal moiety which bindsspecifically to the acceptor site(s).

The unimolecular micelle or "void domain", a three dimensional entity,is critical to this lock and key concept in that it can essentially beconsidered a tertiary structure of the unimolecular micelle system.Since all aspects of the micellar species can be predetermined anddeliberately designed or engineered, the sum of the "void regions" ortotal void domain of the macro-molecule is a designed parametercontained in dendritic building blocks or the activated armed site(s)for molecular attachment of the complementary ligand or key unimolecularmicellar molecule. Hence, the monomers, or building blocks thateventually comprise the resulting unimolecular micelle in still (1) aprimary structure (attributed to nuclei-connectivity), (2) a secondarystructure (attributed to fundamental nuclei interactions such ashydrogen binding, dipole interactions, and London forces), (3) atertiary structure than can assume molecular shapes such as ribbons,zippers, threads, and spheres (internal and external confirmationsinduced by secondary structure), and (4) a dynamic, structured voiddomain or "quasi-tertiary" structure of the unimolecular micelledetermined by the combination of the primary, secondary, and tertiarystructures. The quasi-tertiary domain comprises one of the major domainsof the micellar macro-molecular structure which includes the immediateregion above the micellar surface, the micellar per se, and micellarframework. All of these domains are active in that they can be used toeffect chemical and physical changes of the unimolecular micelle, itsenvironment, a molecular guest or guests, or any of the citedcombinations.

The terminations of the arms or with larger branching, possiblymid-portions of the arms may fold to form an outer surface of themicelle. The surface of the micelle is exposed to immediatelysurrounding environment in which the micelle is disposed. Thisenvironment will have a certain hydrodynamic character, determined byproperties such as pH, lipophilicity-hydrophilicity characteristics.Such surface characteristics also lead to general solubility of themicelle, even when carrying a relatively insoluble guest therein.

The surfaces of the micelles can be readily coated with metal ions.Mono-, di-, and trivalent metals are being possibly bonded directly orindirectly through terminal carboxyl groups or the like, similar to thedissolution of metal ions by most micellar or acidic systems. Likewise,the surface of the micelle can include polar, nonpolar, and/orhydrodynamic group sensitive to pH, ionic or other hydrodynamic changes.The method of making such micelles are disclosed in "Macromolecules" vol27, no 13, 1994, pp. 3464-3472.

The micelles can be characterized as having branches or arms which canbe flexible, each of the arms terminating with a hydrodynamic reactivegroup. The term "flexible" means that the arms are capable of extendingaway from and then, in reverse, folding towards the core atom.Flexibility further describes the relative ability of these arms toextend and contract relative to the core atom. Thusly, as discussedbelow, the branches or arms can be chemically altered such that the armsor branches can extend further or shorter from the core atom therebycontrolling the ability of the micelles to expand in a given environmenthaving no hydrodynamic characteristics. In combination with theflexibility of the arms or branches, the nature of the terminal groupscan also effect the expansion of the micelle in different environments.Thusly, the selection of specific hydrodynamic reactive groups caneffect the relative expansion and contraction of the hydrodynamic radiusof these molecules.

The term "hydrodynamic reactive group" refers to chemical groups whichcan be bound to the terminal ends of arms or branches which are reactivewith outer environment based on the hydrodynamic character of theenvironment. For example, groups such as alcohols, amines, carboxyls,thiols, phosphines, ammonium ions, sulfoniums ions, phosphonium ions,nitrates, sulfates, phosphates, and carboxylates, as well as other knownreactive groups can be modified depending upon the hydrodynamiccharacter of the surrounding environment. For example, hydrodynamicchanges such as pH can proteinate and diproteinate carboxyls and aminesand thereby change the solubility characteristics of these reactivegroups in the environment. Increased solubility in combination withflexibility of the arms or branches of the micelle will result inexpansion of the arms and the concomitant effective increase inhydrodynamic radius of the micelle. Essentially, the molecule becomeslarger. Decreases in the solubility will likewise contract the molecule.

It has been found that with significant increases in length of branchesor arms, the arms or branches may fold into the micelle thereby notnecessarily exposing the terminal end of the arm or branch but rather, amid-section. Accordingly, hydrodynamic groups exposed in this manner canalso effect expansion and contraction of the micelle. The abovedescription of expansion and contraction in response to changes in theenvironment related to the solubility of the branching of the micelle isfurther described in U.S. Pat. No. 5,422,379 to applicants', assigned tothe assignee of the present invention.

The micelles of the present invention can be engineered so that theexpansion of the micelle exposes the opening of the pockets therebyallowing for exposure of the opening of the pocket to ligands disposedin the environment and binding of the acceptor to a complementarymoiety. Contraction of the micelle can fold the branches over theopening of the pocket thereby shielding or masking the void area andacceptor (FIG. 11). Accordingly, the environment of the micelles can bemanipulated to turn on or turn off accessibility to binding of thelocked micelles with ligands such as key micellar molecules describedbelow.

For example, pH, immiscibility or other factors described in the abovementioned patent application Ser. No. 5,422,379 to applicants' can beutilized. For example, an aqueous solution of an acid terminated lockmicelle at pH≧7 would be in an extended (open or porous) configuration.Substrate (guest) molecules are readily encapsulated (dissolved) withinthe lipophilic micelle interior; lowering the solution pH (<4) willcollapse the lock micelle (close the pores) and entrap the key (guest)molecule. This lock-key (host-guest) complex can be isolated from thesolution via filtration methods (such as, dialysis, ultrafiltration, orgel permeation). Dissolution of the isolated lock-key complex in asolution with pH≧7 will facilitate the release of the entrapped keymolecule. The lock micelle imparts its solubility characteristics ontothe entrapped key molecule and should serve as a protective "sheath",which can protect labile functionalities on the key molecule.

It should be noted that the U.S. Pat. No. 5,154,853 to applicants andassigned to the assignee of the present invention (1992) discloses thatunimolecular micelles made in accordance with the present invention havea porosity which is pre-determined, created by the relationships of thebranches, the core defined above, and each of the quaternary areas ortertiary centers (carbon core or nitrogen branching sites, respectively)and created by each additional tier layered thereon. The porosity of theinside core can be changed by increasing or decreasing the distancesbetween the quaternary or tertiary centers; that is, by changing thebranch arm lengths. Hence, pursuant to known art developed byapplicants, the micelles of the present invention can have specificallyengineered aspects of size, porosity, outer surface and internal bindingsites.

As discussed above, the surface character of the micelles made inaccordance with the present invention can be varied. For example, acarboxyl surface can be created, thereby rendering the micelles usefulfor detergents and surfactants, and also reactive to pH.²⁵ Changes in pHwhich increase the solubility of the surface components can expand thedendritic arms, thereby allowing accessibility to the void regions ofthe unimolecular micelle. Returning the pH to its original character canthen contract the dendritic arms, thereby once again enclosing the voidregions. This method of changing solubility of the unimolecular micellesby changing the environment in which the unimolecular micelles areretained can be used to provide accessibility to the void regions forchemical modification, as discussed in detail below.

Besides carboxyl groups, hydroxyl groups, and amines, other acidic,neutral, and/or basic functionalities can be incorporated onto thesurface or on interior dendritic arms adjacent to the void regions ofthese unimolecular micelles as set forth in U.S. Pat. No. 5,154,853. Thevoid areas of these unimolecular micelles made in accordance with thepresent invention have been characterized. The expanded and contractednature of such dendritic arms defining the micelles have also beencharacterized. U.S. Pat. No. 5,422,379 to applicants' discloses variousstructures capable of expansioning contraction for exposure of voidregions and masking of void regions which can be utilized for maskingand shielding the opening to the pockets of the micelles made inaccordance with the present invention, and are incorporated herein byreference.

The branches of the lock micelle can include terminal moieties asdescribed above. The pockets defining the void regions can include whatare termed "gatekeeper" molecules for allowing the entrance of onlyspecifically structured molecules into the opening of the pocket. Thatis, particular molecules can be engineered at the opening of the pocketfor the external environment defining the void region which arechemically selective for particular ligands (and specifically keymicelle molecules as described below) for entrance into the opening ofthe pocket.

For example, the gatekeeper molecules can be selected from the groupincluding, but not limited to, amino acids (such as tryptophan,phenylalanine), carbohydrates and sugars, charged or ionizable groups(including carboxyls, amines, sulfonic acids), metal chelators(including pyridine, phenanthroline, crown ethers, azacrowns), and hostmoieties such as β-cyclodextrin. A particularly useful example is agatekeeper moiety which is a chiral molecule for favoring a singleenantiomer of a guest molecule which can enter the opening of the pocketto bind the acceptor. Accordingly, the present invention can be utilizedas a filtering mechanism for removing a specific enatomer of a moleculefrom a solution.

For example, a lock micelle having an R or S configuration can be usedas either a soluble form or insoluble form bound to a matrix. Tryptophanis an example of a chiral molecule which can terminate a dendriticmacro-molecule as disclosed in the paper entitled "PolytryptophaneTerminated Dendritic Molecules", Newkome et al. Tetrahedron AsymmetryVol 2., No. 10, pp. 957-960, 1991, incorporated herein by reference.Chiral gatekeeper molecules will allow binding of only one of theoppositely active components of a racemic mixture. Accordingly, pursuantto drug industry standards regarding separation of enantiomers (anactive drug component from an inactive drug component) the presentinvention can be used as a filtering system. For example, an aqueoussolution of the acid terminated chiral lock micelle at pH≧7 would be inan extended (open) configuration. Upon addition of a racemic mixture ofa complimentary key, only one enantiomer will interact with the lockmicelle. Lowering the solution pH (<4), will collapse the lock micelleand entrap the preferentially complexed chiral key molecule. This chirallock-key complex can be separated from the solution via filtrationmethods (such as, dialysis or ultrafiltration), removing the remainderof the racemic mixture and other impurities. Dissolution of the isolatedchiral lock-key complex in a solution with pH≧7 will facilitate therelease of the chiral key molecule.

The acceptor is a moiety having a binding region complementary to adesired binding region of a ligand. The combination of an acceptor withan engineered pocket having an opening including gatekeeper molecules asdiscussed above provides a unique family of lock micelle moleculeswherein one ligand (molecule) fits the cavity or structural shape of asecond ligand, such as in a host-guest relationship or nonchemically asa hand in a glove. The structural relationship has a complementary ordernecessary for a docking of one to the other, or molecular complexation.

The structural incorporation of a molecular complimentary binding regioninto the arms of a cascade macromolecule via synthetic proceduresgenerates a molecular lock which is then capable of docking, orcomplexing, with a specific family of molecular complimentary keymaterials. The molecular recognition of this key/lock combinationpermits the molecular incorporation of guest molecules in specific locusor locii permitting an approach to molecular inclusion and encapsulationin a transport domain insulated, for the most part, from the environmentoutside of the cascade (dendritic) macromolecule. Thusly, relativelyinsoluble or enzyme degradable molecules can retain their bioactivitywhile being shielded within the micellar lock and key domain. Uponreaching a binding site having a higher affinity for the guest includingat acceptor region, the guest is released and combined at the receptor.Hence, the present invention provides a guest delivery system.

FIG. 1 provides several examples of the general concept of anacceptor-ligand complimentary relationship. The relationship is notlimited to complimentary units that possess 3H-bonds, but rather it maybe applied to to donor/acceptor units that are based on one or moreH-bonds.

In view of the above, the acceptor as a moiety selected from a groupconsisting essentially or partially charged molecules engineered to becomplimentary to a binding portion of a guest molecule. The acceptor canbe either partially negative, partially positively charge. Specifically,the acceptor can be selected from the group consisting of essentiallypartially charged molecules engineered to be complimentary to a bindingportion of the guest molecule. The acceptor can include at least onepartially negative charge, one partially positive charge or acombination thereof. Specifically, the acceptor can be selected fromgroup including bipyridines, tripyridines, and poly Lewis base moietiescomprised of oxygen, nitrogen, sulfur, phosphorous, halides, ortransition metals with a donor pair of electrons.

The opening of the pocket is predetermined distance from the acceptorfor defining a specific depth that key micelle can be inserted into thepocket to allow only binding of specific key micelles. Again, this addsto the "combination" of the lock for specifying key molecules of apredetermined secondary and tertiary structure.

A key micelle molecule comprises a core molecule and a plurality ofbranches extending therefrom a predetermined distance and at least oneof the branches including a shank portion extending therefrom having aterminal moiety at an end thereof for binding to a complimentaryacceptor of a lock unimolecular micelle. Such a shank portion canconsist essentially of a multicarbon chain, the multicarbon chainincluding zero to 22 carbon atoms. Of course, such a shank portion canbe made by various molecular mechanisms known in the art. But it mustprovide a spacing allowing access of a terminal binding region to anacceptor region within a pocket of a micelle. Examples of such keymicelles or molecules are shown in FIG. 2.

The terminal moiety of the key micellar molecule includes the tertiarystructure including at least one partially charged portion, eithernegative or positive or a combination of the two. Such terminal moietiescan be selected from the group including barbiturates, such asAllobarbitol, Aminoglulehimide, Amobarbitol, Barbituric acid, Barbital,Bemgride, 6-Azauridine, Phenobarbitol, Primidone, Secobarbital,Pentobarbitol, Diazepam, Flurazepam, Methaqualone, Meprobamate, and alsocarbohydrates, such as sucrose, alditols, mannitols, hexoses and aminoacids and peptides such as trytophane, phenylalanine, glycine andnucleotides and nucleosides such as purines and pyrimidines, guanine,cytosine, thiamine, and adenine. As discussed above, the terminal moietycan be chiral.

An advantage of utilizing the present invention is where the terminalmoiety is insoluble in water. The branches of the micelles can includewater soluble moieties bound thereto for rendering the micelle watersoluble. Polarizable groups are water-soluble and when complexed to adonor/acceptor moiety they possess is the potential to make thecompliment water-soluble.

Initial design of this concept, introduces a 2,6-di(acylamino) pyridinemoiety (A) as the "acceptor unit" in the cylinder lock. Suchincorporation is depicted in FIG. 3.

Based on applicants' all-carbon unimolecular micelle model, theacetylene moiety is replaced by the appropriate (poly) functionality.Alternate and more simplified incorporation can be envisioned in FIG. 4,utilizing other related dendrons, or cascade building blocks,(specifically, the aminotris(tert-butyl ester)) previously described inthe applicants' patent application Ser. No. 5,422,379 to applicants' forthe said dendritic building block. Such a process incorporates theacceptor units(s) in the lock; however, the processes herein describedare not limited to only the first tier of construction with four bindingloci (as depicted in FIG. 4), but can be incorporated at highergenerations using known chemistry.

Initial design of the key utilizes the complementary nature of A, thusan imide (CONHCO) moiety fits the model. The case of barbituric acid(IV) was initially used as an example to evaluate this complimentaryrelationship. Barbituric Acid and related materials are depicted in FIG.5.

To illustrate the key/lock principle, four equivalents of the key areadded to the dendritic macromolecule possessing the four lock locii.Each key fits the lock perfectly, resulting in the molecularincorporation of four specific guest molecules within the void domain ofthe macromolecule (FIG. 5). Proof of this concept is by standardspectroscopic procedures. The introduction of other keys possessing thesame complimentary portion but different shaped handles on the "bit"region of the key has been shown to give analogous inclusioned anddocked guest within the lock structure. FIG. 6 shows other relatedexamples in order to establish the facile ability to molecularly securereagents within the cavities of these spherical polymers. The use ofdifferent attachments (Z; FIG. 6) to the barbiturate's unique "bit"region, via an appropriate connector moiety such as an alkyl chain,permits the molecular entrapment of diverse materials within thelipophilic core of these precursors to the water-soluble spheres or thewater-soluble unimolecular micelles. hydrolysis of the lipophilicmacromolecules, e.g. II, to the hydrophilic counterparts does not alterthe docking region within the core. Treatment of III (R═H) which can beobtained by simply the hydrolysis of V (R-tbu). Either route gives riseto a water soluble material processing the inclusioned (locked) guest(key).

The key/lock relationship can be engineered to almost any complimentaryset of organic binding sites. Thus, the complimentary regions can beinterchanged, which is depicted in FIG. 7. Here the inside moiety(CONHCO) is incorporated in the "lock's cylinder". The key now possessesthe di(acylamino)pyridine portion in the unique "bit" region. Themolecular recognition by the formation of three-hydrogen bonds issimilar to the process described in FIGS. 5 and 6.

FIG. 1 illustrates the other possible arrangements of "three pin lockcylinders" (i.e., the physical juxtaposition of hydrogen-bond donor andhydrogen-bond acceptor moieties. Column 1 lists representative examplesof locks and keys; column 2 pictorially shows the molecular recognitionof the locks and keys as being highly specific due to the precisepositioning of partial positive and partial negative charges inherent inthe molecular receptors and donors; column 3 depicts the possibleelectrostatic groupings for a three H-bond lock and key. The lock andkey concept for unimolecular micelles is not limited to three H-bondlocks and keys. Similar complimentary components complexed via 1, 2, (ormore) H-bonds can be envisioned and incorporated into the cascade, ordendritic superstructure.

Alternative keys can use other molecular recognition techniques otherthan hydrogen bonding. The use of metal or several metal center(s) canbe employed in which selective bonding can be shown. FIG. 8 shows thesimplest of complex modes in which the lock and key both possess aterpyridine moiety. The key is converted to the Ru(III) complex, whichcan be introduced to the lock generating the Ru(II) bis-terpyridinecomplex in very high yields. Other metals such as Co(II), Fe(III),Os(II), etc. work equally well.

The terpyridine ligand is nondiscriminatory in complexation with metals;it does, however, form strong complexes and the metal centers can beelectrochemically modified creating a potential catalytic center. Theuse of bipyridine and related bis-amines can generate enhancedselectivity in the recognition process. Lehn and Potts have shown thebis-, tris-, and tetrakis-bipyridines recognize only their counterpartsuch that the bis-bis, tris-tris, and tetrakis-tetrakis are formedselectively even though there may be a mixture of ligands. FIG. 9depicts the key-lock combinations necessary to generate the complexedstructure; the lock would be treated initially with the metal salt,followed by the introduction of the key. If the alternative formation ofthe metal-key it is possible to create boloamphiphile in which two keysare complexed to one (or more) metal ion(s).

It is anticipated that most organic molecules have one or morecomplimentary binding structures. Thus, initially the use of a locuswith two or three hydrogen bonds are capable of bonding thecomplimentary guest with formation of the desired hydrogen bonds.Nucleic bases are used in nature to template or replicate, eg. DNA/RNA.The introduction of these same essential bases with specific lociiwithin the void domain of these cascade macromolecules wouldsynthetically mimic the base pairing; thus, Guanine-Cytosine (similar tothe diacylaminopyridine model with the creation of three hydrogen bondsbetween the bases), Adenine-Thymine (2-hydrogen bonds) would act as thekey/lock complimentary locus holding the complex together.

For more specific keys and locks, multiple adjacent sites enhance thespecificity and/or strength of binding between the key/lock. The use ofpeptide chains can introduce the α-helix arrangement so that thestructure(s) are flexible but capable of generating multiple hydrogenbonds between the lock and key. This α-helical structure is found innumerous proteins, e.g. the fibrous protein myosin and keratin, iseasily incorporated specifically within the void domains of thesemacromolecules.

The following Examples demonstrate the synthesis of key and lockunimolecular micellar molecules made in accordance with the presentinvention.

Generally, the present invention provides a method of makingphysicochemically operative monomer building blocks for synthesis ofcascade polymers. The method includes the steps of acylating aphysicochemically operative moiety including an amino group and amultibranched core alkyne building block including an amino group withan acid chloride to form a physicochemically operative bis amide monomerincluding a physicochemically active portion and a branched portion.Thusly, the present invention provides a monomer or building blockcapable of cascade polymerization addition, whether convergent ordivergent or a combination of the two, for use in the synthesis ofcascade polymers.

The term "physicochemically operative moiety" is meant to mean amolecule capable of having either physiological or chemicalfunctionality inherent unto itself. Examples of such functionalities arechelating capabilities, enzymatic capabilities, quenching capabilities,enzymatic capabilities, quenching capabilities, photosynthesizers,electron sinks, host-guest complexes as well as other chemical andphysiological functions. Unexpectedly, the present invention provides amethod for making a monomer to act as a synthon for the synthesis ofnovel cascade polymers wherein such physicochemically operative moietiesare not only incorporated into the cascade polymer, but are operativemoieties thereby incorporating unique utilitarian functionality into thecascade polymer.

Additionally, the resulting monomer building block includes theoperative functionalities of known building blocks for making cascadepolymers and, in particular, unimolecular micelles. That is, the presentinvention results in a cascade polymer which can function as aunimolecular micelle consisting essentially of a core atom, preferably acarbon atom, and essentially all alkyl arms extending therefrom. Theresult of the inventive method is a physicochemically operative monomer,including a physicochemically active portion and a branched portion andpreferably, if the physicochemically operative moiety is a diamine, anamine functionality. The monomer of the present invention provides thebranching and binding functionalities of a classic monomer for use inthe cascade or tier elongation of a cascade polymer.

The result of the above methods produces a monomer building block of theformula ##STR2## is a physicochemically operative moiety.

EXPERIMENTAL SECTION

Description of the synthesis for the H-bonding locks and keys

General Procedure for the Preparation of Aminopyridine Triester BuildingBlocks for the Incorporation of Bis(amido)pyridine Acceptor Moietieswithin Cascade Superstructures. This Procedure can be used with anybis(acid chloride)!

Aminotriester Building Block (FIG. 4)

A solution of aminotris(tert-butyl ester) (10 g, 0.024 mol)anddiisopropylethylamine (3.11 g, 0.024 mol) in tetrahydrofuran (THF, 50mL) was added to a cold (5° C.), stirred solution of glutaryl dichloride(4.07 g, 0.024 mol) in THF (900 mL) over a period of 3 h. The mixturewas stirred an additional 3 h at 0°-5° C.; subsequently, a mixture ofTHF (50 mL), 2,6-diaminopyridine (7.9 g, 0.072 mol), anddiisopropylethylamine (3.11 g, 0.024 mol) was added in one portion.After stirring for another 12 h and allowing the temperature to rise to25° C., the solvent was removed and the residue dissolved in CH₂ Cl₂(200 mL). Upon washing with H₂ O and saturated brine (2×200 mL portionsof each), the organic phase was dried (Na₂ SO₄), filtered, and thesolvent was removed. Chromatography of the crude product using silicagel and EtOAc/CH₂ Cl₂ as an eluent afforded (5.8 g, 38%) the pureaminopyridine triester.

¹³ C NMR(CDCL₃) δ21.3 (CH₂ CH₂ CH₂), 27.9 (CH₃,CH₂ CO₂), 29.7 (CH₂ CH₂CO₂), 35.7, 36.1 (CH₂ CONH), 57.3 (C(CH₂)₃ !, 80.5 C(CH₃)₃ !, 103.0,104.1 CH(2,4)_(PYR) !, 139.7 CH(3)_(PYR) !, 149.7 (CNHCO_(PYR)), 157.2(CNH₂ PYR) 171.1, 171.8, 172.7 (C═O);

¹ H NMR(CDCL₃) δ1.30 (CH₂ CH₂ CH₂), 1.43 (CH₃), 1.97 (CH₂ CO₂), 1.30(CH₂ CH₂ CH₂, m, 2H), 1.43 (CH₃, s, 27H), 1.97 (CH₂ CO₂, m, 6H) 2.21(CH₂ CH₂ CO₂, CH₂ CONH_(ALKYL), m, 8H), 2.40 (CH₂ CONH_(ARYL), t, 2H,6.7 Hz), 4.56 (NH₂, br s, 2H), 6.09 (NH_(ALKYL)), 6.23 (H₃ (PYR), d, 1H,7.6 Hz), 7.44(H₄ & H₅ (PYR), m, 2H), 8.46 (NH_(ARYL), br s, 1H)

General Procedure for the Preparation the First Tier Poly(pyridino)Cascades (FIG. 4; structure II)

First Tier Poly(pyridino) Dodecaester

A solution of aminopyridine triester (3.0 g, 0.0048 mol) anddiisopropylethylamine (0.624 g, 0.0048 mol) in THF (10 mL) was added inone portion to a solution of tetraacid chloride (0.512 g, 0.0012 mol) inTHF (5 mL) at 0° C. After stirring for 12 h, the solvent was removed andthe residue was chromatographed over silica gel using combinations ofEtOAc/CH₂ Cl₂ with increasing polarities as an eluent to afford (1.6 g,48%) the pure dodecaester (first tier lock).

¹³ NMR(CDCL₃) δ21.5 (CH₂ CH₂ CH₂), 27.9 (CH₃, CH₂ CO₂), 29.7 (CH₂ CH₂CO₂), 35.8, 36.1 (CH₂ CH₂ CH₂), 37.8 (OCH₂ CH₂), 57.3 C(CH₂)₃ !, 66.9,69.5 (CH₂ OCH₂), 80.5 C(CH₃)₃ !, 109.4, 109.6 (C₃,5 (ARYL)), 140.4 (C₄),149.5, 149.7 (C₂,6), 170.5, 171.6 172.0 172.7 (C═O)

¹ H NMR(CDCL₃) δ1.42 (CH₃, s, 108H), 1.98 C(CH₂ CH₂)₃, CH₂ CH₂ CH₂, m,32H!, 2.22 C(CH₂)₃, CH₂ CH₂ CH_(2EXT), m, 32H!, 2.46, 2.59 (CH₂CONHPYRNHCOCH₂, 2×br t, 16H), 3.46 C(CH₂)₄, br s, 8H!, 3.70 (OCH₂)₄, brt, 8H!, 6.27 NHC(CH₂)₃, br s, 4H!, 7.62 (PYRH₄, t, J=8.1 Hz, 4H), 7.84(PYRH₃ & H₅, m, 8H), 8.81, 8.89 (NH_(PYR), 2 br s, 8H)

General Procedure for the Conversion of Poly(tert-butyl esters) toPoly(acids) via hydrolysis with formic acid.

First tier Poly(pyridino) Dodecaacid

The (first tier) dodecatert-butyl ester (1.0 g, 0.36 mmol) was stirredat 40° C. for 15 h in 95% formic acid. The solvent was removed and theresidue was dissolved in hot H₂ O (150 mL) with added charcoal andcelite. The mixture was filtered through a celite pad and the clearcolorless filtrate was evaporated to dryness to afford (0.70 g, 95%) thepure dodecaacid.

¹³ C NMR(CD₃ OD) δ22.7 (CH₂ CH₂ CH₂), 29.2 C(CH₂ CH₂)₃ !, 30.4 C(CH₂)₃!, 36.6, 37.1 (CH₂ CH₂ CH₂), 38.6 (OCH₂ CH₂), 46.5 C₄°), 58.6 (CONHC₄°),68.3 (C₄° CH₂), 70.6 (OCH₂), 110.6, 110.7 (C₃ & C₅)_(PYR), 141.4(C₄)_(PYR), 151.2, 151.3 (C₂ & C₆)_(PYR), 172.8, 174.0, 174.9, 177.2(C═O).

¹ H NMR(CD₃ OD) δ1.95-2.52 (CH₂ CONPYR_(INT), CH₂ CH₂ CH₂, CH₂ CH₂ CO₂H, m, 80H), 3.35 C(CH₂ O)₄, s, 8H!, 3.71 C(CH₂ OCH₂)₄, m, 8H!, 7.70(H₃,4,5(PYR), m, 12H), 8.1 (NH, s)

General Procedure for the Preparation of Poly(t-butyl esters) fromPoly(acids) for the formation of higher generation cascade (dendritic)locks.

Second Tier 36-tert-butyl ester Lock

A mixture of the (first tier) dodecaacid (0.5 g, 0.24 mmol), theaminotris(tert-butyl ester) building block (1.2 g, 0.0028 mol, 12.1 eq),dicyclohexylcarbodiimide (DCC, 0.59 g, 0.0029 mol, 12.1 eq) and1-hydroxybenzotriazol (HBT, 0.39 g, 0.0029 mol, 12.1 eq) was stirred indry N,N-dimethylforamide (DMF, 10 mL) for 12-15 h at 25° C. Afterremoval of the solvent, the residue was dissolved in toluene/diethylether (100 mL, 1:1 v/v) and washed with saturated brine (3×100 mL). Theorganic phase was separated, dried (Na₂ SO₄), filtered, and the solventwas removed. The crude material was chromatographed over silica geleluent (EtOAc/CH₂ Cl₂) aliquots of increasing polarity to afford (0.77g, 48%) the pure second tier, 36-t-butyl ester.

¹³ C NMR (CDCL₃) δ21.6 (CH₂ CH₂ CH₂), 27.9 (CH₃, CH₂ CO₂ R), 29.7 (CH₂CH₂ CO₂)_(G2), (CH₂ CON)_(G1) !, 31.5 (CH₂ CH₂ CON)_(G1), 36.1, 37.7(CH₂ CH₂ CH₂), 46.5(C₄°), 57.4 (CONHC)_(G2),G1, 67.0 C(CH₂ OCH₂)₄ !,69.6 C(CH₂ OCH₂)₄ !, 80.5 C(CH₃)₃ !, 109.8 (C₃ & C₅)_(PYR) !, 140.3(C₄)_(PYR) !, 149.8 (C₂ & C₆)_(PYR) !, 170.8, 172.7 (C═O)

¹ H NMR (CDCL₃) δ1.42 (CH₃, s, 324H), 1.82-2.70 (CH₂ CH₂ CO, CH₂ CH₂CH₂, CH₂ CONHPYR, m, 224H), 3.45, 3.63 (CH₂ OCH₂, 2 br s, 16H), 6.40,7.30 (NHC₄°), 7.68 (C₄(PYR), m, 4H), 7.88 (C₃ & C₅(PYR), m, 8H), 8.95,9.15 (NH.sub.(PYR), 2 br s, 8H)

Second Generation 36-Acid Poly(pyridino) Cascade Lock

Preparation: please see the general procedure for the conversion oftert-butyl esters to acids via formic acid.

0¹³ NMR (CD₃ OD) δ22.6 (CH₂ CH₂ CH₂), 29.2 (CH₂ CO2), 30.4 (CH₂ CH₂ CO₂,CH₂ CON_(G1)), 31.7 (CH₂ CH₂ CON)_(G1), 36.9 (CH₂ CH₂ CH₂), 38.6 (OCH₂CH₂ 46.4 (C₄°), 58.5 (CONHC)_(G2),G1, 68.2 C(CH₂ OCH₂)₄ !, 70.4 C(CH₂OCH₂)₄ !, 110.6 (C₃ & C₅)_(PYR) !, 141.5 (C₄)_(PYR) !. 151.0 (C₂ &C₆)_(PYR) !, 172.9, 174.2, 175.6, 177.3 (C═O);

¹ H NMR (CD₃ OD) δ1.63-2.65 (CH₂ CH₂ CO_(G1),G2, CH₂ CH₂ CH₂, m, 200H)3.35 (C(CH₂ OCH₂), CH₂ CON_(core), CH₂ CH₂ CH₂, br s, 32H), 3.64 (C(CH₂OCH₂, br s, 8H), 7.73 H₃,4,5 pyr, br s, 12H!, 7.35, 7.49, 8.15 (NH).

Synthesis and Characterization of Barbituric Acid Based Keys.11-Bromoundecanamide-triester

A solution of 11-bromoundecanoic acid (10.00 g, 37.7 mmol) dissolved inCH₂ Cl₂ (30 mL) was slowly added to a solution of SOCl₂ (7.0 mL, 94.0mmol) in CH₂ Cl₂ (25 mL). The mixture was refluxed for 5 h, thenconcentrated in vacuo to give 11-bromoundecanoyl chloride, which wasused without further purification: ¹ H NMR (CDCl₃) δ1.26 (bs, (CH₂)₅,10H), 1.34 (m, CH₂ CH₂ CH₂ Br, 2H), 1.67 (m, CH₂ CH₂ COCl, 2H), 1.81 (m,CH₂ CH₂ Br, 2H), 2.85 (t, CH₂ COCl, J=7.2 Hz, 2H), 3.36 (t, CH₂ Br,J=6.8 Hz, 2H); ¹³ C NMR (CDCl₃) δ24.89 (CH₂ CH₂ COCl), 27.95 (CH₂ CH₂CH₂ Br), 28.21, 28.52, 28.84, 29.02, and 29.12 ((CH₂)₅) 32.64 (CH₂ CH₂Br), 33.80 (CH₂ Br), 46.92 (CH₂ COCl), 173.47 (COCl).

A solution of 11-bromoundecanoyl chloride (10.68 g, 37.7 mmol) dissolvedin CH₂ Cl₂ (15 mL) was added to a stirred solution of di-tert-butyl4-amino-4- 2-(tert-butoxycarbonyl)ethyl!-1,7-heptanedioate (15.7 g, 37.7mmol), (i-Pr)₂ EtN (7.32 g, 56.7 mmol), and CH₂ Cl₂ (15 mL) at 0° C. Thereaction mixture was stirred for 2 h at 25° C., filtered, and the CH₂Cl₂ solution washed successively with brine (50 mL), cold 10% HCl (50mL), water (50 mL), saturated NaHCO₃ (50 mL), then dried over anhydMgSO₄, and concentrated in vacuo to give (93%)11-bromoundecanamide-triester, as a white solid: 23.24 g; mp 61.7°-63.9°C.; ¹ H NMR (CDCl₃) δ1.24 (bs, (CH₂)₅, 10H), 1.32 (m, CH₂ CH₂ CH₂ Br,2H) 1.39 (s, OC(CH₃)₃, 27H), 1.47 (m, CH₂ CH₂ CONH, 2H), 1.81 (m, CH₂CH₂ Br 2H), 1.92 (t, CH₂ CH₂ CO₂, 6H), 2.06 (m, CH₂ CONH 2H), 2.18 (t,CH₂ CH₂ CO₂, 6H) 3.36 (t, CH₂ Br, 2H), 5.81 (s, CONH, 1H); ¹³ C NMR(CDCl₃) δ25.67 (CH₂ CH₂ CONH), 27.98 (OC(CH₃)₃), 28.05 (CH₂ CH₂ CH₂ Br),28.63, 29.17, 29.19, 29.25, and 29.28 ((CH₂)₅), 29.75 (CH₂ CH₂ CO₂),29.92 (CH₂ CH₂ CO₂), 32.74 (CH₂ CH₂ Br), 33.88 (CH₂ Br), 37.48 (CH₂CONH), 57.18 (CONHC), 80.52 (OC(CH₃)₃), 172.48 (CONHC), 172.86 (CO₂ C).

Dimethyl malonatoamidotriester

A mixture of 11-bromoundecanamide (10.00 g, 15.1 mmol), dimethylmalonate (5.00 g, 37.8 mmol), NaI (0.565 g, 3.77 mmol), and anhyd K₂ CO₃(6.25 g, 45.2 mmol) in dry DMF (50 mL) was stirred at 90°-100° C. for15-24 h. Upon cooling, the mixture was filtered through celite andconcentrated in vacuo to give a residue, which was dissolved in C₆ H₆(100 mL), washed with water (3×100 mL), dried over anhyd MgSO₄, andevaporated. The resulting crude material was column is chromatographedon basic alumina (C₆ H₁₂ /EtAc; 85/15) to give (56%) the desiredmalonatotriester, as a thick oil: 6.03 g; ¹ H NMR (CDCl₃) δ1.27 (bs,(CH₂)₇, 14H), 1.44 (s, C(CH₃)₃, 27H), 1.59 (m, CH2CH2CONH, 2H), 1.87 (m,CH₂ CH₂ CHCO₂ Me, 2H), 1.97 (t, CH₂ CH₂ CO₂, 6H), 2.11 (t, CH₂ CONH,2H), 2.22 (t, CH₂ CH₂ CO₂, 6H), 3.36 (t, (MeO₂ C)₂ CH, J=7.5 Hz 1H),3.73 (s, CO₂ CH₃, 6H); ¹³ C NMR (CDCl₃) δ25.50 (CH₂ CH₂ CONH), 26.61,27.02, 27.77 (C(CH₃)₃), 28.55, 28.87, 28.96, 29.04, 29.11 (CH₂ CH₂ CO₂),29.14, 29.51 (CH₂ CH₂ CO₂), 29.64 (CH₂ CH), 37.17 (CH₂ CONH), 51.39(CH(CO₂ Me)₂), 52.07 (CO₂ CH₃), 56.97 (CONHC), 80.20 (C(CH₃)₃), 169.62(CO₂ Me), 172.36 (CONH), 172.58 (CO₂ C (CH₃)₃).

Barbituric Acid Key--First Tier Ester.

A stirred solution of the malonatotriester (1.00 g, 1.40 mmol), urea(84.1 mg, 1.40 mmol) and potassium tert-butoxide (314 mg, 2.80 mmol) intert-butanol (5.0 mL) was refluxed for 2 h; water (10 mL) and saturatedaqueous NH₄ Cl (2 mL) was added and the mixture was concentrated invacuo. The resulting material was extracted with CH₂ Cl₂ (25 mL), driedover anhyd Na₂ SO₄, and evaporated to give (90%) the barbituric acidkey, as a thick oil: ¹ H NMR (CDCl₃) δ1.18 (bs, (CH₂)₇, 14H), 1.36 (s,OC(CH₃)₃, 27H), 1.47 (m, CH₂ CH₂ CONH, 2H), 1.88 (m, CH₂ CH₂ CO₂ and CH₂CH₂ CH, 8H), 2.14 (m, CH₂ CH₂ CO₂ and CH₂ CONH, 8H) 3.18 (m, CH₂ CH,1H), 5.8-6.2 (br s, NH, 1H), 8.7 (br, NH, 2H); ¹³ C NMR (CDCl₃) δ25.75(CH₂ CH₂ CONH), 27.90 (C(CH₃)₃), 29.09 (CH₂ CH₂ CO₂), 29.64 (CH₂ CH₂CO₂), 37.29 (CH₂ CONH), 53.10 (CH), 57.29 (CONHC), 80.60 (C(CH₃)₃),162.38 (NHCONH), 172.91 (CO₂), 173.48 (CONHC); 174.71 (CHCONH).

Barbituric Acid Key--First Tier Acid.

Triester (200 mg, 0.422 mmol) was stirred with HCO₂ H (5.0 mL) for 24 hat 25° C., concentrated in vacuo; the last traces of formic acid wereremoved azeotropically via addition of toluene (3×30 mL) to give thedesired triacid, as a thick oil: 150 mg; ¹ H NMR (CD₃ OD) δ1.35 (br s,(CH₂)₇, 14H), 1.63 (m, CH₂ CH₂ CONH, 2H), 1.89 (m, CH₂ CH, 2H), 2.05 (t,CH₂ CH₂ CO₂ H, J=6.8 Hz, 6H), 2.21 (t, CH₂ CONH, J=7.3 Hz, 2H), 2.31 (t,CH₂ CH₂ CO₂ H, J=6.8 Hz, 6H), 3.21 (t, CH, J=7.3 Hz, 1H), 5.75 (brs, NH,1H), 7.41 (brs, NH, 2H).

Experimental Details for H-bonding Lock and Key Complexes.

Preparation of the complexes: Four to one complexes were prepared for ¹H NMR analysis by mixing four equivalents of Key with one equivalent ofLock in the appropriate NMR solvent.

Barbituric acid key (1st tier ester)+First tier dodecaester lock: ¹ HNMR (CDCl₃) δ8.98, 9.10 NH (pyridinocarboxamides), 2×br s, 8H (thesesignals were observed to be shifted downfield by at least 0.2 ppm (J. P.Mathias, E. R. Simanek, and G. M. Whitesides, J. Am. Chem. Soc. Vol.116., pp 4326-4340, 1994)!, 7.63, 7.84 (pyr-H₃,4,5, sharp multiplets,12H, these absorptions were observed to sharpen relative to the parentLock) All other pertinent absorptions were observed at chemical shiftslisted in the experimental section.

Barbituric acid key (1st tier ester)+second tier 36-acid lock: ¹ H NMR(DMSO-d⁶) δ10.05 NH (pyridinocarboxamides), s, 8H (these signals wereobserved to be shifted downfield by at least 0.2 ppm !, 7.76(pyr-H₃,4,5, br s, 12H), these absorptions were observed to sharpen andcoalescese relative to the parent Lock) All other pertinent absorptionswere obsevered at chemical shifts listed in the experimental section.

Synthetic Method and Expermental Details for the Preparation of MetalCoordinated Locks and Keys.

General Procedure for the Coupling of the Hydroxyalkylacids with Cltpy

To a stirred suspension of powdered KOH (1.82 g, 32 mmol) and4-hydroxybutyric acid, sodium salt (0.63 g, 5 mmol) dissolved in 40 mldry DMSO, 4'-chloro-2;2':6',2"-terpyridine (1.33 g, 5 mmol) was added.The mixture was stirred for 1 h at 25° C., and then heated to 65° C. for20 h. After cooling 40 ml of ice-water was added and the mixture wasacidified to pH 6 with 10% HCl. The precipitate that was formed wasfiltered, washed with water and dried in vacuo to give the purelock-0-acid 1.1 g (66%).

General Procedure for the Amid-Coupling

A mixture of the lock-0-acid (1.34 g, 4 mmol), dicyclohexylcarbodiimide(DCC; 866 mg, 4.2 mmol), and 1-hydroxybenzotriazole (1-HBT; 567 mg, 4.2mmol) in 20 ml DMF was stirred at 25° C. for 1 h.Di-tert-butyl-4-amino-4- 2-(tert-butoxycarbonyl)ethyl!-heptanedioate(1.66 g, 4 mmol) was added to the mixture, which was stirred at 25° C.for additional 23 h. After filtration of dicyclohexylurea, the solventwas removed in vacuo to give a residue, which was dissolved in EtOAc andfiltered through a short Alumina column. The filtrate was concentratedin vacuo, and chromatographed (SiO₂ column) eluting with CH₂ Cl₂ /EtOActo give the pure lock-3-ester as a colorless solid 1.26 g (43%).

General Procedure for the Ester-Hydrolysis

A solution of the the lock-3-ester (915 mg, 1.25 mmol) in 95% formicacid (10 ml) was stirred at 25° C. for 20 h. After concentration,toluene was added and the solution was again evaporated to removeazeotropically any residual formic acid. No further purification isnecessary to give the lock-3-acid in quantitative yield.

Preparation of the key-Ru-complex

A suspension of the key-9-ester (280 mg, 0.15 mmol), and RuCl₃.3H₂ O (39mg, 0.15 mmol) in abs. EtOH (10 ml), was refluxed for 20 h. The solventwas evaporated in vacuo and the crude product was chromatographed on anAlumina column with Methanol to give the key-3-ester RuCl₃ as a brownresidue 177 mg (57%).

Preparation of the key and lock complexes

Lock-9-ester (65.5 mg, 0.037 mmol), and 4-ethylmorpholine (4 drops) wereadded to a suspension of key-3-ester-RuCl₃ (77 mg, 0.037 mmol) in MeOH.The mixture was heated to reflux for 1.5 h and after cooling an excessof methanolic ammoniumhexafluorophosphate was added. The solvent wasevaporated in vacuo and the resulting residue was chromatographed onSiO₂ eluting with Acetonitrile/aqu. KNO₃ 7:1 to give thekey-9-ester-Ru-lock-9-ester-complex as a deep red solid 90 mg (65%).

Incorporation of 2,6-diamidopyridine moieties into dendriticmesomolecules.

This examples demonstrates the incorporation of 2,6-diamidopyridinemoieties into dendritic mesomolecules and examine their ability to formH-bonded complexes with imide groups.

Preparation of early generation polypyridino dendrimers was facilitatedby employing high-dilution conditions for the connection of threestructural components. As shown in FIG. 11, addition of one equivalentof aminotris(tert-butyl ester) I and diisopropylethylamine to glutaryldichloride or dodecanedioyl dichloride, followed by addition of excess2,6-diaminopyridine yielded (35-40%) the extended dendrons 2a and 2b,respectively Evidence for the formaton of arylamine 2a includesabsorptions in the ¹³ C NMR spectrum at 47.3, 35.7, 36.1, 171.1, 171.8and 172.7 ppm corresponding to CONHC₄°, 2×NHCOCH₂, and 3×C═O,respectively. Five peaks (¹³ C NMR) were also recorded for the pyridinering carbons at 103.0, 104.1 (C₃,5), 139.7 (C₄), 149.7 (C₂), and 157.2(C₆) ppm. Arylamine protons (NH₂) were observed (¹ H NMR) at 4.56 ppm,while the amide proton signals occurred at 6.09 NH.sub.(ALK) ! and 8.46ppm NH.sub.(AR) !. Nearly identical ¹ H and ¹³ C NMR spectra wererecorded for the related elongated amino triester 2b.

Arylamine 2a was subsequently acylated via reaction with propionoyl togive the diamidopyridine triester 3. Tetrakisdiamidopyridine 4 was thenconstructed by the treatment of a poly(acid chloride) (5; see FIG. 12)with 2-amino-6-N-propionoylpyridine. Support for these structures (3 and4) included the expected NMR absorptions as well as signalscorresponding to the CH₂ CH₃ groups (30.6 and 9.5 ppm; ¹³ C NMR).

Acylation of four equivalents of the triester 2a with tetrahedral core⁹5 provided the 1^(st) tier, tetrapyridine, dodecaester 6a (FIG. 12).Formation of polyester 6a was indicated by the disappearance of ¹ H NMRpeaks at 4.56 (NH₂) and 6.23 ppm H₅(PY) !, the appearance of absorptionsat 8.89 and 8.81 ppm 2×CONH.sub.(AR) !, and the downfield shift of thesignals attributed to the pyridyl protons 7.84 (H₃,5) and 7.62 ppm(H₄)!. Additional supporting ¹³ C NMR resonance's included four C═Oabsorption's and five distinct aromatic peaks 109.4, 109.6 (C₃,5), 140.4(C₄), 149.5, and 149.7(C₂,6) ppm! suggesting a "polar gradient"proceeding from the central carbon to the periphery. Reaction of amine2b (4 equivalent with the core 5 gave the corresponding extendeddodecaester 6b as supported by similar ¹ H and ¹³ C NMR spectra observedfor 6a.

Synthesis of a second generation polypyridine dendrimer was effected bydeprotection of 12-ester 6a to give dodecaacid 7a as evidenced by thedisappearance of peaks attributed to the tert-butyl ester moietiesfollowed by reaction with amine 1 (12 equivalent) to afford 36-ester 8.Support for the conversion includes the appearance of ¹³ C NMR signalsat 27.9 (CH₃) and 29.2 (CH₂ CH₂ CO₂) ppm as well as at 57.4 and 80.5 ppmcorresponding to the new branching C₄° 's and t-butyl C₄°'srespectively. Heteroaromatic peaks appeared as broadened absorptions at109.8 (C₃,5), 140.3 (C₄), and 149.8 ppm (C₂,6). The ¹ H NMR spectrumrecorded the expected signals as well as two broadened resonances at8.95 and 9.12 ppm (pyridine carboxamide protons). Treatment of the36-ester 6 with formic acid gave the water soluble 36-acid 7. Conversionof more lipophilic dodecaester 6b to the corresponding 12-acid 7b (HCO₂H) proceeded smoothly; however, repeated attempts to prepare the 2ndtier, 56-ester via the DCC/1-HBT acid-amine coupling were unsuccessful.

Free barbituric acid, which is only sparingly soluble in CD₃ CN,exhibits a very broad downfield absorption for the imide moieties;whereas, it is freely soluble to the limit of complementary complexationin the presence of the bisamidopyridine dendrimers. Notably, nodiscernible change in the ¹ H NMR spectrum using the corresponding thirdtier dendrimer⁹, lacking internal recognition sites, was observed in thepresence of barbituric acid. Chemical shift changers for the complexedNH moieties, even in this competing solvent, corresponded to ca. 0.1 ppmfor both generation dendrimers. Spectra obtained at 60° C. recordedupfield imide absorptions at 8.75 ppm suggesting internal H-bonding inthe free host; thus, accounting for self association, the Δδ of theimide peak corresponds to 0.3 to 0.4 ppm.

The ¹ H NMR titration experiments (in CDCl₃) for the determination ofhost (3, 4, and 6a):guest H-bonding association constants employedglutarimide primarily due to its 1:1 docking potential (unsubstitutedbarbituric can complicate data interpretation due to 2:1 complexformation). Glutarimide solutions were titrated with known amound of theindividual hosts.¹⁰ Chemical shift changes of the monopyridine's (3)carboxamide protons (a maximum of 0.5 and 0.7 ppm downfield for each NH)were plotted versus imide concentration (FIG. 13a). Associationconstants of K_(a) =62.1 and K_(a) =66.6 were determined for each NH.FIG. 13b plots the titration data using glutarimide and tetrapyridinecore 4 (a maximum of 0.7 ppm for each pyridinecarboxamide NH; K_(a)=69.8 and 69.9). Constants derived from these experiments are alsocomparable with reported values for similar hosts:guest complexes.³,11FIG. 13c represents the titration of glutarimide with the firstgeneration, tetra(bisamidopyridine) dendrimer 6a. The change inpyridinecarboxamide proton shift upon final titration with glutarimidecorresponds to 0.1 and 0.2 ppm for each NH. The magnitude of theseshifts corresponds well with that observed for the barbituric acid guestand further supports the postulated self association. A curvedcorrelation suggests a more complicated guest:host relationship than inthe previous examples or formulation of higher order aggregates. Otherfactors potentially affecting this relationship and resulting weakassociations as indicated by the small NH chemical shifts dendrimercomplexation of 3'-aziod-3'-deoxythimidine (AZT) exhibited morepronounced downfield shifts of the participating protons! includeinefficient donor-acceptor alignment, the potential for hostself-association, and the availability of additional complexation sites(i.e., CONH and CO₂ R moieties; K_(a) ≈46 M⁻¹). However, these findingssupport specific host:guest(s) interactions; although, additionalcoordination sites might weakly compete for the guest(s).

Molecular modeling of the polyesters (6 and 8) reveals an ca. 20 Ådistance (extended conformation) from the central carbon to the firsttier branching point suggesting ample room for guest inclusion.

Experimental Data

The following compounds were made and analyses in accordance with thepresent invention.

Lock-0-acid C₁₉ H₁₇ N₃ O₃ (335)

¹ H-NMR (CDCl₃ /MeOD): δ=2.21 (CH₂, m, J=6.9 Hz, 2H), 2.59 (CH₂ CO, t,J=7.3 Hz, 2H), 4.33 (CH₂ Otpy, t, J=6.2 Hz, 2H), 7.46 (C⁵ H, tm, J=5.6Hz, 2H), 7.93 (C^(3') H, s, 2H), 7.98 (C⁴ H, tm, J=8 Hz, 2H), 8.60 (C³H, dm, J=8 Hz, 2H), 8.67 (C⁶ H, dm, J=4.9 Hz, 2H).

¹³ C-NMR (CDCl₃ /MeOD): δ=25.73 (CH₂), 31.63 (CH₂ CO), 68.63 (CH₂ Otpy),108.68 (C^(3')), 123.16 (C³), 125.48 (C⁵), 138.75 (C⁴), 150.01 (C⁶),157.26 (C²), 158.38 (C^(2')), 168.60 (C^(4')), 177.00 (CO₂ H)

Lock-3-ester C₄₁ H₅₆ N₄ O₈ (732)

¹ H-NMR (CDCl₃): δ=1.40 (C(CH₃)₃, s, 27H), 1.98 (CCH₂, t, 6H), 2.15(CH₂, m, 2H), 2.21 (CCH₂ CH₂, t, 6H), 2.35 (CH₂ CON, t, 2H), 4.26 (CH₂Otpy, t, 2H), 5.99 (NH, s, 1H), 7.32 (C⁵ H, tm, 2H), 7.82 (C⁴ H, tm,2H), 8.00 (C^(3') H, s, 2H), 8.60 (C³ H, dm, 2H), 8.67 (C⁶ H, dm, 2H).

¹³ C-NMR (CDCl₃): δ=25.06 (CH₂), 28.02 (C(CH₃)₃), 29.83 (CH₂ CO), 30.05(CCH₂), 33.43 (CH₂ CON), 57.46 (C-quat), 67.22 (CH₂ Otpy), 80.63(OCC(CH₃)₃), 107.37 (C^(3')), 121.28 (C³), 123.74 (C⁵), 136.70 (C⁴),148.99 (C⁶), 156.10 (C²), 157.12 (C^(2')), 167.02 (C^(4')), 171.48(CON), 172.86 (CO₂ C(CH₃) ₃).

Lock-3-acid C₂₉ H₃₂ N₄ O₈ (564)

¹ H-NMR (MeOD): δ=2.10 (CH₂ ; CCH₂, m `br`, 8H), 2.38 (CCH₂ CH₂, t, 6H),2.43 (CH₂ CON, t, 2H), 4.12 (CH₂ Otpy, t, 2H), 7.47 (C⁵ H, t, 2H), 7.70(C^(3') H, s, 2H), 7.93 (C⁴ H, t, 2H), 8.35 (C³ H, d, 2H), 8.60 (C⁶ H,d, 2H).

¹³ C-NMR (MeOD): δ=26.21 (CH₂), 29.60 (CH₂ CO), 30.81 (CCH₂), 33.75 (CH₂CON), 58.96 (C-quat), 69.47 (CH₂ Otpy), 109.26 (C^(3')), 123.53 (C³),126.45 (C⁵), 139.94 (C⁴), 149.62 (C⁶), 154.42 (C²), 155.87 (C^(2')),169.47 (C^(4')), 174.87 (CON), 177.42 (CO₂ H).

Lock-9-ester C₉₅ H₁₄₉ N₇ O₂₃ (1755)

¹ H-NMR (CDCl₃) δ=1.40 (C(CH₃)₃, s, 81H), 1.95 (CCH₂, m, 24H), 2.17 (CH₂; CCH₂ CH₂, m, 26H), 2.38 (CH₂ CON, t, 2H), 4.26 (CH₂ Otpy, t, 2H), 6.13(NH, s `br`, 3H), 6.17 (NH, s `br`, 1H), 7.28 (C⁵ H, tm, 2H), 7.80 (C⁴H, tm, 2H), 7.98 (C^(3') H, s, 2H), 8.58 (C³ H, dm, 2H), 8.65 (C⁶ H, dm,2H).

¹³ C-NMR (CDCl₁₃): δ=25.14 (CH₂), 27.99 (C(CH₃)₃), 29.76 (CH₂ CH₂ CO),33.42 (CH₂ CON), 57.41 (C-quat), 67.49 (CH₂ Otpy), 80.46 (OCC(CH₃)₃),107.44 (C^(3')), 121.20 (C³), 123.64 (C⁵), 136.59 (C⁴), 148.94 (C⁶),156.09 (C²), 157.00 (C^(2')), 167.05 (C^(4')), 172.38 (CON), 172.76 (CO₂C(CH₃)₃), 172.99 (3CON).

Lock-9-acid C₅₉ H₇₇ N₇ O₂₃ (1251)

¹ H-NMR (MeOD): δ=2.00 (CH₂ ; CCH₂, m, 26H), 2.30 (CCH₂ CH₂, m, 24H),2.48 (CH₂ CON, t, 2H), 4.28 (CH₂ Otpy, t, 2H), 7.50 (C⁵ H, t, 2H), 7.85(C^(3') H, s, 2H), 7.98 (C⁴ H, t, 2H), 8.52 (C³ H, d, 2H), 8.68 (C⁶ H,d, 2H).

¹³ C-NMR (MeOD): δ=26.53 (CH₂), 29.56 (CH₂ CO), 30.76 (CCH₂), 34.18 (CH₂CON), 58.87 (C-quat), 69.33 (CH₂ Otpy), 109.19 (C^(3')), 123.54 (C³),126.13 (C⁵), 139.55 (C⁴), 150.02 (C⁶), 156.07 (C²), 157.07 (C^(2')),169.20 (C^(4')), 175.30 (CON), 175.80 (3CON), 177.45 (CO₂ H)

Key-0-acid C₂₇ H₃₃ N₃ O₃ (447)

¹ H-NMR (CDCl₃): δ=1.33 (CH₂, s `br`, 12H), 1.50 (CH₂, m, 2H), 1.65(CH₂, m, 2H), 1.85 (CH₂, m, 2H), 2.32 (CH₂ CO, t, 2H), 4.21 (CH₂ Otpy,t, 2H), 6.9 (CO₂ H, `br`, 1H) 7.34 (C⁵ H, tm, J=4.9 Hz, 2H), 7.85 (C⁴ H,tm, J=7.9 Hz, 2H), 7.97 (C^(3') H, s, 2H), 8.60 (C³ H, dm, J=7.9 Hz,2H), 8.72 (C⁶ H, dm, J=4.9 Hz, 2H).

¹³ C-NMR (CDCl₃): δ=24.79 (CH₂), 25.77 (CH₂), 28.87 (4CH₂), 28.97(2CH₂), 29.15 (CH₂), 34.21 (CH₂ CO), 68.23 (CH₂ Otpy), 107.58 (C^(3')),121.56 (C³), 123.82 (C⁵), 136.95 (C⁴), 148.90 (C⁶), 156.17 (C²), 156.85(C^(2')), 167.42 (C^(4')), 178.06 (CO₂ H).

Key-3-ester C₄₉ H₇₂ N₄ O₈ (844)

¹ H-NMR (CDCl₃): δ=1.18 (CH₂, s `br`, 12H), 1.24 (C(CH₃)₃ s, 27H), 1.30(CH₂, m, 2H), 1.45 (CH₂, m, 2H), 1.70 (CH₂, m, 2H), 1.82 (CCH₂, t, 6H),2.00 (CH₂ CON, t, 2H), 2.08 (CCH₂ CH₂ t, 6H), 4.04 (CH₂ Otpy, t, 2H),5.99 (NH, s , 1H), 7.15 (C⁵ H, t, 2H), 7.67 (C⁴ H, t, 2H), 7.82 (C^(3')H, s, 2H), 8.44 (C³ H, d, 2H), 8.50 (C⁶ H, d, 2H).

¹³ C-NMR (CDCl₃): δ=25.65 (CH₂), 25.79 (CH₂), 28.87 (CH₂), 2913 (2CH₂),29.19 (CH₂), 29.33 (CH₂), 29.37 (2CH₂), 29.67 (CCH₂), 29.85 (CCH₂ CH₂),37.39 (CH₂ CON), 68.04 (CH₂ Otpy), 80.40 (OC(CH₃)₃), 107.25 (C^(3')),121.16 (C³), 123.57 (C⁵), 136.56 (C⁴), 148.81 (C⁶), 156.03 (C²), 156.85(C^(2')), 166.90 (C^(4')), 172.47 (CON), 172.74 (CO₂ C(CH₃)₃).

Key-3-acid C₃₇ H₄₈ N₄ O₈ (676)

¹ H-NMR (CDCl₃): δ=1.28 (CH₂, s `br`, 12H), 1.38 (CH₂, m, 2H), 1.58(CH₂, m, 2H), 1.72 (CH₂, m, 2H), 2.08 (CCH₂, m, 6H), 2.20 (CH₂ CO, t,2H), 2.34 (CCH₂ CH₂, m, 6H), 4.00 (CH₂ Otpy, t, 2H), 7.41 (C⁵ H, t, 2H),7.68 (C^(3') H, s, 2H), 7.90 (C⁴ H, t, 2H), 8.40 (C³ H, d, 2H), 8.60 (C⁶H, d, 2H).

¹³ C-NMR (CDCl₃): δ=27.08 (CH₂), 27.31 (CH₂), 29.51 (2CH₂), 30.10 (CH₂),30.47 (2CH₂), 30.57 (2CH₂), 30.73 (6 CCH₂ CH₂), 37.89 (CH₂ CO), 58.68(C-quat), 69.99 (CH₂ Otpy), 108.90 (C^(3')), 123.26 (C³), 126.03 (C⁵),139.39 (C⁴), 149.73 (C⁶), 155.36 (C²), 156.55 (C^(2')), 169.17 (C^(4')),176.12 (CON), 177.29 (CO₂ H).

Key-9-ester C₁₀₃ H₁₆₅ N₇ O₂₃ (1867)

¹ H-NMR (CDCl₃): δ=1.20 (CH₂, s `br`, 12H), 1.30 (C(CH₃)₃, s, 81H), 1.38(CH₂, m, 2H), 1.50 (CH₂, m, 2H), 1.76 (CH₂, m, 2H), 1.86 (CCH₂, m, 24H),2.10 (CH₂ CO; CCH₂ CH₂, m, 26H), 4.12 (CH₂ Otpy, t, 2H), 5.98 (NH, s,1H), 6.07 (NH, s, 3H), 7.21 (C⁵ H, t, 2H), 7.73 (C⁴ H, t, 2H), 7.90 (C³'H, s, 2H), 8.50 (C³ H, d, 2H), 8.58 (C⁶ H, d, 2H).

¹³ C-NMR (CDCl₃): δ=25.61 (CH₂) 25.74 (CH₂), 27.86 (C(CH₃)₃), 28.83(CH₂) 29.22 (2CH₂), 29.36 (3CH₂), 29.58 (18CH₂), 29.75 (6CH₂), 31.56(CH₂), 31.89 (CH₂ CO), 57.16 (C-quat), 67.98 (CH₂ Otpy), 80.26(OC(CH₃)₃) 107.15 (C^(3')), 121.07 (C³), 123.53 (C⁵), 136.51 (C⁴),148.77 (C⁶), 155.95 (C²), 156.79 (C^(2')), 167.11 (C^(4')), 172.43 (CO₂C(CH₃)₃), 172.72 (3CON), 172.81 (CON).

Lock-9-ester-Ru-key-9-ester C₁₉₈ H₃₁₄ N₁₄ O₄₆ Ru (3723)

¹ H-NMR (CDCl₃): δ=1.30 (CH₂, s, 12H), 1.40 (C(CH₃)₃, s, 81H), 1.43(C(CH₃)₃, s, 81H), 1.60 (CH₂, m `br`, 4H), 1.93 (CH₂, m `br`, 48H), 2.20(CH₂, m, `br`, 52H), 2.55 (CH₂, m `br`, 4H), 4.10 (CH₂ Otpy, t, 4H),6.03 (NH, s `br`, 1H), 6.18 (NH, s `br`, 3H), 6.46 (NH, s `br`, 4H),7.19 (C⁵ H, m, 4H), 7.38 (C⁴ H, m, 4H), 7.65-8.80 (C^(3') H; C³ H; C⁶ H,m, 12H).

¹³ C-NMR (CDCl₃): δ=25.89 (CH₂), 28.07 (C(CH₃)₃), 29.79 (CH₂), 31.78(CH₂), 32.20 (CH₂), 33.59 (CH₂), 57.21, 57.36 (C-quat), 80.36, 80.52(OC(CH₃)₃), 111.13, 111.55 (C^(3')), 124.52 (C³), 127.72 (C⁵), 137.82,138.18 (C⁴) 151.98 (C⁶), 155.99, 156.12 (C²), 158.24 (C^(2')), 166.23,168.26 (C^(4')), 172.70, 172.77 (CO₂ C(CH₃)₃), 172.95 (CON).

The above Examples demonstrate the method of making, and using thepresent invention. Other uses of the present invention can be achievedthrough the cross-linking of such molecules having multiple lock and keyportions. Also, the turning on and turning off of the binding portionsand specificity for binding various molecules such as drug molecules,provide for the use of the present invention as drug delivery systemswhere the drug is either irreversibly or reversibly bound at theacceptor site.

The invention has been described in an illustrative manner, and it is tobe understood the terminology used is intended to be in the nature ofdescription rather than of limitation.

Obviously many modifications and variations of the present invention arepossible in light of the above teachings. Therefore, it is to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described.

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What is claimed is:
 1. A monomer building block of the formula ##STR3##is a physicochemically operative moiety.
 2. A monomer as set forth inclaim 1 wherein the physicochemically operative moiety is selected fromthe group consisting of chromophoric quinones, bipyridines, piperazines,pyrimidines, dyes, diazo units, alkenes, alkynes, amines, alcohols,thiols, carboxylic acids, masked isocyanates, and aromatic centerscapable of metal-arene complex formation.
 3. A monomer as set forth inclaim 1 wherein the said physicochemically operative moieties arediamines.
 4. A monomer building block of the formula ##STR4## is aphysicochemically operative moiety.